Preparation of derivatives of cholesterol

ABSTRACT

Process for the production of hydroxylated derivatives of cholesterol and 7-dehydrocholesterol which comprises subjecting a saturated unsubstituted or substituted derivative of cholestane, dissolved in a suitable solvent, in the presence of peracetic acid, to irradiation with ultraviolet radiation having a wavelength less than 350 m Mu , separating the reaction products, which if desired, are converted to other derivatives, and recovering the residue of the starting material. Novel derivatives are obtained and these are: 3 Beta -acetoxy,25hydroxy,5 Alpha -cholestane; 3 Beta -acetoxy,5 Alpha ,25dihydroxy cholestane; 3 Beta ,5 Alpha ,25-trihydroxy cholestane; 3-keto,5 Alpha ,25-dihydroxy cholestane; 3-keto,25-hydroxy- Delta 4-cholestane; 3-keto-25-hydroxy- Delta 4,6-cholestadiene.

Uni ed States Patent [191' Mazuret al.

[4 Nov. 18, 1975 PREPARATION OF DERIVATIVES OF CHOLESTEROL Inventors:Yehuda Mazur, l4 l-laknesset Hagdola St., Tel-Aviv; Avner Rotman, 8Hagoren St., Rehovot, both of Israel Filed: Mar. 25, 1974 1 Appl; No.:454,394

Foreign Application Priority Data Apr. 1, 1973 "US. Cl 204/l57.1 R

Int. Cl. B01J 1/10 FieldofSearch 204/158 References Cited UNITED STATESPATENTS v 5/1968 Schenck et al., 204/158 R Israel 41923 3,476,77911/1969 Vezina et a1. 204/158 R Primary Examiner-Howard S. WilliamsAttorney, Agent, or Firm-Hubbell, Cohen, & Stiefel -keto,5a,25-dihydroxy cholestane; 3-keto,25-hydroxy- N-cholestane;3-keto-25-hydroxy-A -cholestadiene.

5 Claims, No Drawings PREPARATION OF-DERIVATIVES OF I CHOLESTEROLBACKGROUND OF .TfiieiNvENnou I I According to the present inventionthere is provided a novel and simple process for the preparation ofhydroxylated derivatives of cholesteroliand of .7'-dehy-'droxycholesterol, which are intermediates in the preparation of theseand of other hydroxylated derivatives of cholecalciferol.

SUMMARY OF THE INVENTION The present invention relates to thepreparation of hydroxylated derivatives of cholesterol and7-dehydrocholesterol and to the preparation of cholecalciferol and ofderivatives of that compound. I

The process of the present invention comprises subjecting a saturatedunsubstituted or substituted cholestane derivative, dissolved in asuitable-solvent, in the presence of peracetic acid, to irradiation withultrayiolet light having a wavelength less than 350 mp, resulting in theintroduction of hydroxy groups in the tertiary position of thecholestane skeleton.

As the main product of the reaction there is obtaine the 25-hydroxyderivative of the starting'material, and its yield is of the order ofabout 10 percent. Thus 33- acetoxy,5a-cholestane (I) and3B-acetoxy,5a-hydroxy cholestane (II) resulted in the corresponding 25-hydroxy derivatives, (III) and (IV). In addition to these, furthertertiary-hydroxylated derivatives were isolated.

Thus, for example, (II) gave in addition to (IV) also the l4/3-OI-I (V);l'7a-OI-I (VI); a-OI-I(VIII), 2013- OH (IX) derivatives, see Table.

The derivatives (IV) to (IX) were converted by a sequence of reactionsteps to the corresponding hydroxylated 7-dehydrocholesterolderivatives. The sequence of reaction steps is illustrated withreference to the reaction of (IV): Compound (IV) was hydrolyzed withmethanolic potassium hydroxide. to 3B,5a,25-choles- ,tane-trio (X); thiswas oxidized by means of chromic acid to the corresponding3-keto-derivative (XI). The latter was dehydrated with acid to thecorresponding A -3-keto-derivative (XII). Compound (XII) was convertedby heating with chloranil to the corresponding 3-keto-4,6-diene (XIII)which was acetylated by means of acetic anhydride and then reduced withsodium borohydride to the desired -hydroxy-7-dehydrocholesill 'iafsicltlirrron OFIETHIEHPREFERRJED ,EMBODIMENT Examplell A solution of 15 gof 3B-acetoxy-5a-choles'tane in 250 cc of ethyl acetate was treated withcc of peracteic acid IOpercnt) in acetic acid and was irradiated withuiv. light of about 300 mu. wavelength for 24 hours. Theresultingreaction mixture was washed consecutively with an aqueoussolution of sodium bisulfite, sodium bicarbonate and water and thesolvents were evaporated in vacuo to dryness. The residue waschrorn-atographed on a column of silica gel to give l.5 g of the novel3B-acetoxy-25-hydroxy-5a-cholestane, m.p. l80l8lC and 1.2 g of the known3B-acetoxy-5ahydroxy-cholestane, m.p. l"25 l2 6C.

Example 2 A solution of g 3B-acetoxy-5-a-hydroxy cholestane in 25 ml.ethyl acetate was treated with 100 ml. of peraceticlacid (70 percent) inacetic acid and was irradiated with u.v. light of about 300 mp"wavelength for 12 hours. The resulting. reaction mixture waswashed witha solution of aqueous sodium bisulfite, sodium bicarbonate and then withwaterfAfter evaporation of the solvent in vacuo the' residue waschrornotographed on a column of silica 'gel to give 10g of the new 33--acetoxy-5a,25-dihydroxy cholestane (IV) which was recrystallised frommethanol, m.p. 2,1 6 2l7-C and a "mixture consisting of3fl-acetoxy-5Ex,l4fi dihydroxycholestane (V), 3 B-acetoxy,5a, l7a-dihydroxy-cholestane (VI), 3 B-acetoxy,5 a, l 7B-dihydroxy-cholestane (VII), SB-acetoxy-S a,20a-dihydroxy cholestane (VIII), 3B-acetoxy,5a,ZOB-dihydroxy-cholestane (IX).

Example 3 terol (XIV). The conversion of (XII) to (XIV) is effected byconventional means, similar to those described with reference to thepreparation of 7-dehydrocholesterol derivatives by Pelc et al., J. Chem.Soc. (C)

The A -3-keto-cholestanederivative (XII) was converted to itsenol-acetate derivative (XV) which was reduced with sodium borohydrideto the 25-hydroxycholesterol. In the same way the related A -3-ketonesderived from the compoundV toIX gave the respective hydroxy-cholesterolderivatives.

Example 4 Example 5 A solution of 950 mg of3-keto-5a,25-dihydroxycholestane in 200 ml of benzene was refluxed for2.5 hours in the, presence of 200 mg of p-toluene sulfonic acid. Thecompound was isolated with ether and chromatographed on silica gel togive 600 mg of the known 3-keto-25-hydroxy-A -cholestane, m.p. 15 3 1 55C.

( Example 6 A solution of 50 mg 3-keto 25-hydroxy-A-cholestane in ml oft-butanol was refluxed for 44 hours in 3;920,5 3.1 3 4 the presence of120 mg of chloranil. The reaction mix- We claim: ture was filtered, thefiltrate was evaporated to dryness l. A process forvproducinghydroxylated derivatives and the residue chromatographed on silica gelto give of cholesterol and 7-dehydrocholesterol, which com- 35 mg of3-keto-25-hydroxy-N' -chOIeStadiene, m.p. prises subjecting a saturatedunsubstituted or substil75l77C.

ACO AcO AcO 5 tuted derivative of cholestane, dissolved in a suitable vAcO AcO

solvent, in the presence of peracetic acid, to irradiation 65 withultra-vlolet.hght havmga wavelength less than ing material is3fl-acetoxyjd-cholestane and one of the 350 mp, separating the productsof the reaction and reo i th id f th Starting i L products is thecorresponding 25-hydroxy derivative.

2. A process as ciai ni ed in l, iivhereih the start- 5. A process asclaimed in claim 4, wherein there are also obtained3/3-acetoxy,5a,l4B-dihydroxy-cholestane; 3B-acetoxy, 5a,l7a-dihydroxycholestane; 3/3- acetoxy-5a,l7B-dihydr0xy cholestane; BB-acetoxy-5a,20a-dihydroxy cholestane and 3/3-acetoxy, 501,203-

dihydroxy cholestane.

1. A PROCESS FOR PRODUCING HYDROXYLATED DERIVATIVES OF CHOLESTEROL AND7-DEHYDROCHOLESTEROL, WHICH COMPRISES SUBJECTING A SATURATEDUNSUBSTITUTED OR SUBSTITUTED DERIVATIVE OF CHOLESTANE, DISSOLVED IN ASUITABLE SOLVENT, IN THE PRESENCE OF PERACETIC ACID, TO IRRADIATION WITHULTRA-VIOLET LIGHT HAVING A WAVELENGTH OF LESS THAN 350 MU, SEPARATINGTHE PRODUCTS OF THE REACTION AND RECOVERING THE RESIDUE OF THE STARTINGMATERIAL.
 2. A process as claimed in claim 1, wherein the startingmaterial is 3 Beta -acetoxy,5 Alpha -cholestane and one of the productsis the corresponding 25-hydroxy derivative.
 3. A process as claimed inclaim 2, wherein a further product is 3 Beta -acetoxy,5 Alpha -hydroxycholestane.
 4. A process as claimed in claim 1, wherein the startingcompound is 3 Beta -acetoxy,5 Alpha -hydroxy cholestane and the productcomprises 3 Beta -acetoxy,5 Alpha -25-hydroxy cholestane.
 5. A processas claimed in claim 4, wherein there are also obtained 3 Beta -acetoxy,5Alpha ,14 Beta -dihydroxy-cholestane; 3 Beta -acetoxy, 5 Alpha ,17 Alpha-dihydroxy cholestane; 3 Beta -acetoxy-5 Alpha ,17 Beta -dihydroxycholestane; 3 Beta -acetoxy-5 Alpha ,20 Alpha -dihydroxy cholestane and3 Beta -acetoxy, 5 Alpha ,20 Beta -dihydroxy cholestane.